Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y and P2Y as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor.

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y and P2Y on the platelet. The clinical effectiveness of inhibiting P2Y has been well established, and preclinical studies indicated that the inhibition of P2Y could provide equivalent antithrombotic efficacy as P2Y antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1-imidazole scaffold of our previously reported xanthine oxidase inhibitor , we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y and P2Y. We described the structure-activity relationships of the 2-phenyl-1-imidazole compounds, which led to the identification of the most potent antiplatelet agents, and , both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that and could be promising drug candidates.